Electron paramagnetic resonance (EPR) oximetry with intratumoral implantation of an oxygen-sensitive paramagnetic material (India ink) was used to monitor repeatedly the pO2 in individual murine tumors before and after split dose irradiation. Results confirmed our previously reported time course in radiation-induced-fibrosarcoma (RIF-1) murine tumors of pO2 changes of increased hypoxia 24 hr after irradiation and maximum reoxygenation at about 72 hrs. Tumor growth was used to compare the response in a "hypoxic" group where the second dose of radiation was delivered at the minimum post-radiation tumor pO2 (24 hr after initial irradiation) to an "oxic" group where the second dose of radiation was delivered after reoxygenation had occurred (72 hr interval between doses). There were significantly longer tumor doubling times in the "oxic" compared to the "hypoxic" group, indicating that the measured pO2 changes reflected changes in tumor radiosensitivity. A 24 hr interval between doses resulted in a delay of reoxygenation in the tumors, while a 72 hr interval resulted in a second cycle of hypoxia/reoxygenation. Our results suggest that repeated direct measurements of pO2 in tumors by EPR oximetry could be useful in timing split radiation doses to achieve improved local control of tumors.